Burden and attributable risk factors of ischemic stroke in China from 1990 to 2019: an analysis from the Global Burden of Disease Study 2019

Background The epidemiologic characteristics and attributable risk factors of ischemic stroke in China have changed over the past three decades. An up-to-date analysis on deaths, disability-adjusted life-years (DALYs), prevalence, incidence, and attributable risk factors of ischemic stroke for China is needed. This study aims to provide a comprehensive analysis of burden and attributable risk factors of ischemic stroke at national level in China by sex from 1990 to 2019. Methods This is a secondary analysis of the Global Burden of Disease (GBD) study 2019. All data used in this study was derived from the 2019 GBD study. Deaths, DALYs, prevalence, incidence, and attributable risk factors of ischemic stroke in China by sex from 1990 to 2019 were analyzed. Results From 1990 to 2019, the age-standardized deaths rate decreased by 3.3%, age-standardized DALYs rate decreased by 4%, age-standardized prevalence rate increased by 33.5%, and age-standardized incidence rate of ischemic stroke in China increased by 34.7%. In 2019, ambient particulate matter pollution became an important risk factor, whereas household air pollution from solid fuels was no longer a major risk factor for ischemic stroke in China. Burden of ischemic stroke was higher in China compared to other regions. Ambient particulate matter pollution among men, and diet high in sodium, smoking, household air pollution from solid fuels among women account for the increased deaths/DALYs due to ischemic stroke in China. Conclusion Our study revealed that great changes have occurred in burden and attributable risk factors of ischemic stroke in China in the past three decades. Distinct sex-specific differences are observed in burden and attributable risk factors.


Introduction
Globally, stroke is the second leading cause of death and the third leading cause of death and disability combined in 2019 (1). In China, stroke has become the top leading cause of death at the national level (2). In the past three decades, the epidemiologic characteristics and attributable risk factors of stroke in China have changed a lot (3). Ischemic stroke accounts for over 80% of all stroke cases (4). In 2019 alone, there were 2.87 million (95% uncertainty interval 2. 38-3.46) new ischemic stroke cases in China (3). However, to date, a specific quantitative analysis of the time trends and gender differences of ischemic stroke in Chinese population is not available. Although several studies have investigated some respects of burden and risk factors of ischemic stroke in China, deeper analyses on the changes of epidemiologic characteristics and attributable risk factors are still needed (3,5,6).
The Global Burden of Disease (GBD) study of 2019 is the latest database that reports global estimates of various diseases (7). It provides an important tool for researchers to analyze disease burden and attributable risk factors around the world. A GBD 2019 stroke analysis showed that the age-standardized incidence rate of all stroke types in China decreased by 9.3%, whereas the age-standardized incidence rate of ischemic stroke increased by 34.7% (3). The disease burden of ischemic stroke is still severe in China. In this study, we investigated the time trends and gender differences of ischemic stroke burden and attributable risk factors in China between 1990 and 2019 based on the GBD study 2019. The burden and risk factors of ischemic stroke in China were compared to that of other countries. Differences in epidemiologic characteristics and attributable risk factors between men and women were observed. Results of this study will provide a reference for Chinese health policy makers to perfect public health policy of ischemic stroke prevention and control in the future.

Overview
The GBD study 2019 was designed to present epidemiological data and associated risk factors of diseases over time from 1990 to 2019 (7). The GBD database utilizes systematic or hierarchical sampling, ensuring equal chance of selection. The proportion of the population covered depends on data source availability and quality for each subgroup. The trends of disease burden of ischemic stroke in China were estimated using the following standard epidemiological measures: deaths, disability-adjusted life-years (DALYs), years lived with disability (YLDs), years of life lost (YLLs), prevalence, and incidence. Methods of extracting data from the GBD study have been described elsewhere (7). The 95% uncertainty intervals were determined by extracting the 25th and 975th values from the ordered set of values obtained from 1,000 posterior draws (8). This study was performed in accordance with the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER) (9). Ethical approval was not required as this study was based on publicly available data (GBD 2019) and no personal data was collected.

Case definitions
According to WHO criteria, stroke was defined as rapidly developing clinical signs of disturbance of cerebral function lasting more than 24 h or leading to death (10). In GBD study 2019, stroke was classified into three subcategories, consisting of ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage (3). Ischemic stroke was defined as an episode of neurological dysfunction due to limited blood flow to brain tissue and subsequent infarction (11).

Measures of burden
The measures of disease burden include deaths, DALYs, YLDs, YLLs, prevalence, and incidence of ischemic stroke by sex and age from 1990 to 2019. The Cause of Death Ensemble modelling (CODEm) method was used to estimate ischemic stroke-specific deaths (12). DALYs were used as common indicators to measure the disease burden of specific causes, consisting of the burden caused by YLDs and YYLs. YLDs were calculated as the prevalence of ischemic stroke multiplied by the corresponding disability weights (13). YLLs were calculated as the number of deaths cause by ischemic stroke multiplied by the remaining standard life expectancy at the age of death (14). Prevalence was defined as the number of newly confirmed cases and previous cases during the study period (3). Incidence was defined as the occurrence of first-ever ischemic stroke according to the criteria mentioned above (1). DisMod-MR 2.1, a Bayesian meta-regression modelling tool, was used to estimate the prevalence and incidence of ischemic stroke (15).

Risk factor estimation
Exposure to risks that exceeding the theoretical minimum risk exposure level (TMREL) was included to estimate risk factors due to ischemic stroke burden (16). Estimates of attributable risk factors were generated at the most detailed level. Risk factors included in this study consists of three series: environmental risks (ambient particulate matter pollution, household air pollution from solid fuels, high temperature, low temperature, and lead exposure), behavioral risks (smoking, secondhand smoke, alcohol use, and low physical activity), and metabolic risks (high systolic blood pressure, high low-density lipoprotein cholesterol (LDL), high fasting plasma glucose, high bodymass index (BMI), kidney dysfunction, diet high in sodium, diet high in red meat, diet low in whole grains, diet low in fruits, diet low in fiber, and diet low in vegetables). The risk factors were ranked according to the age-standardized ischemic stroke-related DALYs by year and sex (1). The correlations between disease deaths/DALYs rates and risk factors in corresponding years were analyzed using linear regression. Statistical analysis was performed using GraphPad Prism and a p-value of less than 0.05 was considered statistically significant.
Death rates of ischemic stroke increased with age, especially markedly after 60 years old ( Figure 2). DALY rates also increased with age, except for above 90 years old. In 2019, the highest DALY rate of ischemic stroke was in the 85-89 years of age (21294.4 per 100,000 people). After 50 years old, prevalence and incidence rates of ischemic stroke rose rapidly. The prevalence rates in Chinese elder population were significantly higher in 2019 compared to 1990. Incidence rates increased with age in both 1990 and 2000. Interestingly, the incidence rates reached their peaks in the 80-84 years of age in both 2010 and 2019 (1238.9 and 1326.4 per 100,000 people, respectively). The YLD rates in elder population were significantly higher in 2019 compared to 1990 (Supplementary Figure S2). YLL rates also increased with age, except for above 90 years old. Distinct gender differences were observed in all indicators.

Burden of ischemic stroke by SDI and income
Globally, regions were divided into five groups according to the SDI value (18). The age-standardized death and DALY rates of ischemic stroke in high and high-middle SDI groups decreased markedly from 1990 to 2019 (−53.4% and-38.3%, respectively; Figure 3). However, age-standardized death and DALY rates in China and other SDI groups hardly changed in the past 30 years. China had the highest increase in age-standardized prevalence and incidence rates of ischemic stroke among all the groups (33.5 and 34.7%, respectively). Furthermore, China had the highest age-standardized death, DALY, prevalence, and incidence rates in 2019. World Bank classified global regions into four groups according to income levels: high, upper middle, lower middle, and low (19). Similar to above results, China had the highest age-standardized death, DALY, prevalence, and incidence rates of ischemic stroke among all the income groups in 2019 (Supplementary Figure S3). The disease burden of ischemic stroke in China was also compared with global and Asia levels, as well as with three similar countries with large population and territory (India, USA, and Brazil). The results showed that China still had the highest age-standardized death, DALY, prevalence, and incidence rates among the six groups ( Figure 4). USA had the lowest age-standardized death and DALY rates and India had the lowest age-standardized prevalence and incidence rates in the past three decades.

Changes in risk factors of ischemic stroke in China from 1990 to 2019
In China, metabolic risks were the first leading risk factors for ischemic stroke deaths and DALYs from 1990 to 2019 (Table 2; Figure 5). An interesting finding was that behavioral risks were the second leading risk factors for males but environmental risks were the second leading risk factors for females. From 1990 to 2019, detailed Frontiers in Neurology 04 frontiersin.org risk factors attributable to ischemic stroke deaths and DALYs had made profound changes. The first leading risk factor for ischemic stroke was high systolic blood pressure in the last three decades ( Figure 6). Household air pollution from solid fuels was the second leading risk factors in 1990 and downed to 11th by 2019 ( Figure 7). In contrast, ambient particulate matter pollution rose from 7th to 2th.
Smoking was an important risk factor for ischemic stroke deaths and DALYs in males, but not a vital factor for females. High systolic blood pressure was a common risk factor for all SDI groups. In 2019, high BMI was less important risk factors, and ambient particulate matter pollution and diet high in sodium were more vital factors for China compared to high SDI group (Figure 8). Compared to low SDI group, household air pollution from solid fuels was less important, and ambient particulate matter pollution, smoking, and diet high in sodium were more important risk factors for China. For USA, high fasting plasma glucose and high BMI were more important for ischemic stroke DALYs (Figure 9). For India, high fasting plasma glucose was the second leading risk factor for ischemic stroke. For Brail, ambient particulate matter pollution and diet high in sodium were not important but high fasting plasma glucose and high BMI were very important risk factors for ischemic stroke. Gender difference was also observed here. For example, smoking was a more important risk that inducing ischemic stroke for males in China than the other three countries.

Correlation analysis
The correlations between age-standardized deaths/DALYs and risk factors in corresponding years were analyzed in this study. Ambient particulate matter pollution was associated with ischemic stroke-induced deaths rate increase in males (R 2 = 0.859, p < 0.001), but not associated with females (R 2 = 0.068, p = 0.163) in the past 30 years in China ( Figure 10). Diet high in sodium and smoking were both associated with increase of death rates due to ischemic  Figure S4). Additionally, high fasting plasma glucose, high LDL cholesterol, and high systolic blood pressure were all associated with ischemic stroke-specific death/DALY rates increase, regardless of males and females (Supplementary Figures S5, S6). Trends in number, rate, and age-standardized rate for deaths, DALYs, prevalence, and incidence of ischemic stroke by sex in China from 1990 to 2019.

Discussion
To our knowledge, this is the first study that comprehensively analyzed the disease burden and attributable risk factors of ischemic stroke in China from 1990 to 2019 base on the GBD study 2019.
In this study, the changes in burden and risk factors of ischemic stroke from 1990 to 2019 were described at the national level of China. The changes in China were compared to regions with different SDI and income in the world. Our results showed China has faced new challenges on ischemic stroke preventing and controlling.
In the past three decades, the absolute number of deaths, DALYs, YLDs, YLLs, prevalence, and incidence due to ischemic stroke increased substantially in China. The large increase may be explained by the changes in the demographic structure such as ageing and population growth (1). However, age-standardized death and DALY rates of ischemic stroke did not change significantly during the last 30 years. The age-standardized ischemic stroke death and DALY rates even decreased by 3.3 and 4%, respectively. The advancements were probably attributed to significant improvements of living condition and medical care in China over the past three decades (20). The age-standardized prevalence and incidence rates increased markedly, which may be partly due to improvement in diagnostic level and increase in unhealthy life styles (e.g., smoking, diet high in red meat, high BMI) (21).
Gender is an important factor influencing the disease burden of ischemic stroke (22). The age-standardized death and DALY rates due to ischemic stroke were greater in males than in females, which suggests that ischemic stroke is more harmful to men than women. The results of YLD and YLL also suggest that men are more likely to die and women are more likely to disability after attacked by ischemic stroke. This is probably because men are more likely than women to have unhealthy lifestyles, such as smoke and drink (23). Moreover, higher level of estrogen in females might also contribute to this situation because of the neuroprotective effects of estrogen (24). Interestingly, we found that age-standardized prevalence and incidence rates in males were lower than in females, suggesting that women are more likely to have ischemic stroke than men. This finding contradicts results from previous studies (25,26). Racial disparity and age variability might probably explain this paradox.
It is well known that age is a major risk factor for ischemic stroke (27). The overall death rate of ischemic stroke in China is increasing with age, especially for elderly over 70 years old. However, we found that death rate among males decreased over 95 years old after 2000. That may Frontiers in Neurology 07 frontiersin.org be because men over 95 years old are more likely to suffer from other fatal diseases (26). The incidence rate of ischemic stroke increased with age in 1990 and 2000, but decreased with age in people over 85 years old in 2019 (especially in females). The incidence rate among females was higher than males between 60 to 80 years old. But after 80 years old, incidence rate among males was higher than females. This finding is different from previous study (28). Further study is needed to investigate the sex difference of ischemic stroke burden among very old people. The prevalence rate among females was significantly higher than males over 60 years old. One possible explanation is that estrogen in women decreases rapidly after menopause (24). Higher death rate in males may be also accountable for this situation. In addition, the changes in DALY rate attributable to ischemic stroke are largely determined by YLL rate. SDI reflects the comprehensive level of social development. Globally, increase in SDI accompanied by decrease in stroke burden over time (11). The ischemic stroke burden of China were the highest among all the SDI groups in 2019, suggesting the serious situation faced by China. The high deaths and DALYs of ischemic stroke in China were mostly due to the high deaths and DALYs among Chinese males. Additionally, China has the fastest growth rates in incidence and prevalence of ischemic stroke during the past 30 years. Many factors such as rapid economic development, increased environmental pollution, and intensified aging population may be involved (29, 30). The burden of ischemic stroke in China were still the highest among all groups with different income levels. China, USA, India, and Brazil are highly representative large countries in terms of geographical coverage and population, making them comparable on a global scale. Compared to these countries, the burden of ischemic stroke in China were still the highest. Among the three countries, USA has the lowest death and DALY and India has the lowest incidence and prevalence. There are still huge gaps in the prevention and controlling of ischemic stroke for China despite great progress has been made. Metabolic risks were the most important risk factors attributable to ischemic stroke in China (31,32). Behavioral risks were the second most important risk factors among males and environmental risks were the second most important risk factors among females. The reason may be that men smoke and drink significant more than women (33). High systolic blood pressure remained the first leading risk factor for ischemic stroke in the past 30 years (34). However, other risk factors have changed a lot over time. Household air pollution from solid fuels used to be a vital risk for ischemic stroke but it became unimportant now. The Chinese government's efforts to expand the use of clean fuels (e.g., marsh gas and solar energy) might account for this change (35). Furthermore, ambient particulate matter pollution has become the second leading risk for FIGURE 3 Trends in age-standardized rate for deaths, DALYs, prevalence, and incidence of ischemic stroke by sex in different SDI regions from 1990 to 2019. ischemic stroke in China (36). Rapid growth of motor vehicles and increased urbanization in China during the past two decades might lead to this result (37,38). Smoking remained the second important risk factor after hypertension for males in China (39). Diet high in red meat and high BMI are becoming increasingly important risks for ischemic stroke. Unhealthy eating habits and overweight are becoming more common in Chinese population, which should catch our attention (40).
Risk factors attributable to ischemic stroke distinctly differ in regions with different SDI levels. High BMI was an important risk for ischemic stroke in high SDI regions in 2019. Whereas in low SDI regions, high BMI was less important and household air pollution from solid fuels remained a major risk. In China, differed with them, ambient particulate matter pollution and diet high in sodium were vital risks for ischemic stroke. The main cause of China's growing environmental FIGURE 4 Trends in age-standardized rate for deaths, DALYs, prevalence, and incidence of ischemic stroke by sex in four big countries from 1990 to 2019. pollution is the sharp rise in energy consumption that accompanied rapid development in the past 30 years (41). Sodium intake is high in China may be due to the high-salt eating habits of Chinese population (42). Among big countries, ambient particulate matter pollution was an important risk in China and India. Rapid economic development in these two countries in the past three decades might account for this (43). For USA and Brazil, high BMI was a more important risk attributable to ischemic stroke. In India, household air pollution from solid fuels was more severe and the diet in red meat was significantly less. This was probably associated with the life style and religious custom of Indians. We also analyzed the correlation between deaths/DALYs and risk factors in corresponding year. This indicator reflects whether a specific risk was involved in increased burden of ischemic stroke during the past 30 years in China. We found that ambient particulate matter pollution was associated with increase of deaths/DALYs in males rather than in females. This result was differed from previous studies and should be studied further (44-46). Diet high in sodium among females rather than males was associated with deaths/DALYs increase. This may be because that women are more salt-sensitive than men (47). Interestingly, we found that smoking in females rather than in males was relevant to increased deaths/DALYs due to ischemic stroke. This result, in agreement with previous studies, that women are more susceptible to smoking effects than men (48,49). Household air pollution from solid fuels was more relevant with increased deaths/ DALYs in females rather than in males. This might be partly because that women cook more frequently than man (50,51).
Many similar studies have been published to study the disease burden of stroke based on the GBD database. A lot of studies have analyzed the global burden of stroke and its risk factors (1,11,52). At the national level of China, the burden of stroke has also been analyzed systematically by many researchers (3,5,6,53,54). In the aspect of ischemic stroke, the global burden of ischemic stroke has been well studied (55)(56)(57). However, the disease burden and risk factors of ischemic stroke in China has not been comprehensively analyzed. To the best of our knowledge, this study is the first one to comprehensively analyze the burden and attributable risk factor of ischemic stroke in China base on GBD study.

Limitations
This study has several limitations. First, estimates in this study was generated using GBD data and methodologies. Although data from GBD database is generally considered to be reliable, audience should also be aware of the general limitations of GBD study (58, 59). Second, we were not able to provide analysis on epidemiologic changes of ischemic stroke at provincial level in China due to the limited data in GBD study 2019. Third, analyses on the ischemic stroke subtypes (e.g., large artery atherosclerosis, small vessel occlusion, cardioembolism, other determined aetiology, and undetermined aetiology) (60) were unable to conduct because the GBD framework did not classify ischemic stroke. Despite these limitations, this study provides useful information for us to know the current status of ischemic stroke burden and risk factors in China using available data.

Conclusion
The present study revealed that the disease burden of ischemic stroke in China is still severe. There is much room for improvement in terms of ischemic stroke preventing and controlling situation in China, compared with other countries in the world, especially with developed countries. Distinct gender differences in disease burden and risk factors were observed during the 30-year observation period. Risk factors for ischemic stroke in China had changed a lot from 1990 to 2019. Public health policy should be adjusted accordingly with the changed situation to better reduce the burden of ischemic stroke.

Data availability statement
The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

Author contributions
YY, X-YX, and DL conceived this study. YY and Y-TZ accessed and acquired the raw data, performed the primary analysis, prepared tables and figures, and drafted the first manuscript. J-CZ, H-LZ, R-WF, Y-XJ, and H-QH contributed to the interpretation of the data. X-YX critically revised the manuscript. All authors reviewed the article, read the final manuscript and approved the submission.

Funding
This study was supported by the National Natural Science Foundation of China (grant nos. 82074193 and 81903942) and Peking University Medicine Seed Fund for Interdisciplinary Research (grant no. BMU2018MX027).

Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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